Connecting Epigenetics and Memory to PTSD
1 in 5. That is the statistic for Iraq and Afghanistan war veterans that have been diagnosed with Post-Traumatic Stress Disorder (PTSD), according to the Department of Veteran Affairs. PTSD is a severe psychological condition that can develop after witnessing traumatic events, and its symptoms include disturbing flashbacks, anxiety, distress, and numbing of the memory altogether. Some people respond to traumatic events more dramatically than others, and how they react to trauma can be pinpointed to certain molecular mechanisms, such as the epigenetic modifications of DNA methylation and hydroxymethylation in the brain. Scientists in the Jaenisch and Tsai labs at Massachusetts Institute of Technology are looking more closely at the relationship between epigenetics, neurological pathways, and cognitive processes, specifically focusing on Ten-eleven translocation (Tet) proteins. Tet proteins catalyze the oxidation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC). It is a combination of three proteins, Tet1, Tet2, and Tet3, that work together to reduce DNA methylation levels in the active demethylation pathway. Out of the three Tet proteins, Tet1 in particular has been shown to have a role in active DNA demethylation in the brain and lowering DNA methylation levels by reducing 5-mC to 5-hmC. Tet proteins are expressed to their highest levels in the brain and therefore, there has been a growing interest within the neuroscience field regarding the role of Tet proteins. In order to learn more about neurological effects of DNA methylation and hydroxymethylation, Rudenko et al. have recently published findings on the effect of Tet1 on neuronal gene expression and memory extinction.
In their studies, the researchers used mice that contain a Tet1 knockout (Tet1KO) to compare against normal mice expressing Tet1. Tet1KO mice, when compared to control mice, showed similar brain structure and health. Even through behavioral tests like the Morris water maze and Pavlovian fear conditioning, Tet1KO mice exhibited similar behaviors in memory acquisition, anxiety, and depression traits in comparison with normal mice. However, Tet1KO mice displayed impairment in memory extinction, the process of replacing older memories with newer memories. Memory extinction showcases the brain’s cognitive flexibility in adapting to changes. This impairment was demonstrated when Tet1KO mice were fear conditioned in one cage through shock pulses and then placed into another cage and still exhibited “freezing” or paralysis from fear, even when there were no more shock pulses. On the other hand, normal mice were fear conditioned in the same manner in one cage and when placed into a new cage without shock pulses, the normal mice did not exhibit as much “freezing” as they learned they were in a safe cage. Furthermore, the Tet1KO mice also showed abnormal long-term depression (LTD) through single-pulse, low frequency stimulation. LTD is one of the key factors in synaptic plasticity of neurons, and where synapses strengthen or weaken over time is the essential basis for learning and memory.
To further study this behavioral anomaly from Tet1KO mice at the molecular level, the authors investigated gene expression changes between Tet1KO and normal mice. Microarray analysis and quantitative real-time PCR data showed down regulation of multiple neuronal activity regulated genes such as Npas4, c-Fos, Arc, Egr2, and Egr4 in Tet1KO mice. The authors also investigated epigenetic modifications in the Tet1KO mice, relative to the control mice, using bisulfite sequencing and global quantification of 5-mC and 5-hmC through mass spectrometry. They found increased levels of DNA methylation in the Npas4 promoter region of Tet1KO mice, along with corresponding decreases in DNA hydroxymethylation in this same region. Npas4 is a plasticity-related neuronal gene and is considered critical for cognitive regulation. Therefore, epigenetic repression of this gene due to loss of Tet1 may account for behavioral differences observed in Tet1KO mice.
This study provides a new point of view about the function of Tet proteins in the brain, both behaviorally and molecularly. Rudenko et al. illustrate the significance of Tet1 in the role of memory extinction and neuronal gene regulation in the brain through epigenetic changes. Connecting the function of Tet1 to memory extinction may help explain the molecular reasoning for PTSD and lead scientists and doctors to help patients manage with their psychological issues more directly.
Rudenko A, Dawlaty MM, Seo J, Cheng AW, Meng J, Le T, Faull KF, Jaenisch R, & Tsai LH (2013). Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. Neuron, 79 (6), 1109-22 PMID: 24050401